Heat can STING: Defining the relationship between heat and cGAS/STING activation in iTreg and Th1 CD4+ T cells 2260369

Abstract Introduction Heat is a cardinal feature of inflammation that is also generated by many solid tumors. We have recently shown that heat promotes Th1-mediated inflammation via cGAS/STING activation, and also decreases suppressive capacity of regulatory T cells (Tregs) with no detectable STING activation. The cGAS/STING pathway detects cytosolic nucleic acids, inducing Type I Interferon (IFN-I) production and stimulating T cell immunity when activated in innate cells. It is also highly expressed in T cells, yet the CD4+ T cell-intrinsic effects of STING remain underexplored, and are especially unclear within regulatory T cells. Methods Given the pro-inflammatory effects of heat, and the likelihood that Tregs are exposed to heat while suppressing inflammation, we explored the effects of STING and heat (39 °C) on induced Tregs (iTregs) compared to Th1 cells. Results Notably, we have found that STING activation reprograms iTregs into IFN-I-producing T helper-like cells with inflammatory function accompanied by decreased oxidative metabolism and suppressive function. Both heat and STING increased ROS and DNA damage in iTreg and Th1 cells, and activating STING at 39 °C revealed that heat potentiates STING-induced inflammation in iTregs and Th1s, but Th1s experienced significantly more cell death in response to cGAMP and/or heat. Our data show that Th1 cells have increased expression of cGAS/STING at 39 °C, and at baseline (37 °C) compared to iTreg cells, indicating a potential mechanism for the resilience of iTreg cells during cell stress responses to heat and STING activation. Conclusion These data suggest a novel axis linking heat to STING that can be leveraged to understand and modulate Treg function in inflammation and promote CD4+ T cell responses without inducing significant cell death. These findings motivate further investigation into the mechanisms intertwining STING and heat in Tregs and suggest potential synergy between temperature and Treg-targeted STING modulators for broad applications in immunotherapies. Funding Source NIAID (F31AI186436) Topic Categories Cellular Adhesion, Migration, and Inflammation (CAM)